The present invention relates to a non crosslinked block polymer.
It also relates to a process for the preparation thereof and to the use thereof particularly in pharmaceutical compositions.
The block polymer according to the invention contains sequences of polyethylene glycol linked to sequences of polyester and/or polycarbonate. The polyester sequences are selected in particular from polyfumarate, polymaleate and polysuccinate sequences.
The most advantageous polyester sequences according to the present invention are polyfumarates and polysuccinates.
Polysuccinates and polyfumarates have been described in patent application EP0043976 and have already been tested for their use in pharmaceutical compositions but were ruled out because of their highly hydrophobic nature and their poor biodegradability.
Nevertheless, the Applicant company has succeeded in developing polymers containing said polyesters which are particularly suitable for use in pharmaceutical compositions.
The Applicant company has, in fact, discovered that the insertion of hydrophilic sequences of polyethylene glycol polymers into chains of polyfumarate, polysuccinate and polymaleate improves the biocompatibility of said polymers whilst reducing the toxicity thereof.
The block polymer according to the present invention has the following general formula (I):
xe2x80x94[Paxe2x80x94(Pbxe2x80x94Pc)sxe2x80x94Paxe2x80x2xe2x80x94Pdxe2x80x94Pe]z
wherein:
z=1 to 20,
s=0 to 25,
Pa represents:
xe2x80x94[COAxe2x80x94COOB]xe2x80x94t
xe2x80x83where:
t=1 to 150, and
A represents CHxe2x95x90CH or CH2xe2x80x94CH2 
B represents (CH2)nxe2x80x94Oxe2x80x94 where n=1 to 8,
Pb and Pd, each independently, represent:
xe2x80x94[COO]xe2x80x94x
where x=0 or 1;
Pc and Pe, each independently of one another, represent:
[RO]u
xe2x80x83where:
u=0, to 150, and
R represents an alkyl, cycloalkyl, alkenyl, alkynyl or aryl group, optionally substituted,
Paxe2x80x2 represents
xe2x80x94[COAxe2x80x94COOBxe2x80x2]xe2x80x94txe2x80x2
where A has the same meaning as above
B represents (CH2)nO, where n =0 to 8 or [RO]u, R and u being defined as above,
and txe2x80x2=0 to 150;
provided that if s=0, txe2x80x2=0, x=0 and u=0 then B does not represent (CH2)4O if A is CH2CH2.
The weight-average molecular mass of the polymer is in the range 2,000 daltons to 300,000 daltons.
The polyethylene glycol (PEG) sequences introduced into the polymers according to the present invention may be linked either directly to the polyesters or by way of polycarbonate linkages.
The advantage of introducing PEG by way of polycarbonate linkages lies in the fact that the degradation of the polymers may be modified depending on the number and length of the polycarbonate sequences introduced into the polymer.
The presence of polycarbonate sequences has the effect of retarding the rate of degradation.
Thus, the polymers according to the invention allow great flexibility in terms of the choice of their biodegradability and hydrophilic properties. In fact, it is possible to modify the biodegradability and hydrophilic properties of the polymer by altering:
the number of polycarbonate sequences and the number of PEG sequences in each unit of the polymer,
the length of the hydrophobic and hydrophilic sequences in each unit of the polymer,
the length of the polymer.
The presence of hydrophilic PEG increases the water solubility of the polymer whilst reducing its immunogenicity. Moreover, the introduction of PEG sequences as described by M. NAGATA et al. in Polymer International, Vol. 42, permits better biodegradability of the polyfumarates and polysuccinates. In fact, for the same weight of polymer, the biodegradability is greater in the presence of PEG.
The polymers according to the present invention may have a very high molecular weight, from 20,000 daltons upwards, whilst remaining soluble and biodegradable. Said high molecular weight polymers may be concentrated on tumours by targeting the tumour cells by an effect known as xe2x80x9cEnhanced Permeability Retention Effectxe2x80x9d (EPR). In fact, the vascular walls of tumour cells are more permeable to macromolecules than the vascular walls of healthy cells.
The proportion of PEG sequences in the polymer also makes it possible to prepare soluble or insoluble polymers which may be used as supports for active principles in pharmaceutical compositions or for antigens in vaccines. Said polymers may, therefore, be used in the formation of implants, microspheres, microparticles or nanoparticles in combination with active principles. The nanoparticles will be composed of polymers with superior biodegradability in order to obtain more rapid release of the active principle. The implants, microspheres or microparticles will allow controlled release of the active principles.
The polymers according to the invention may also be conjugated with an active principle. By way of example, these active principles may be selected from anti-inflammatories, anti-tumour agents, immunosuppressants, anti-thrombotics, neuroleptics, anti-depressants, anti-hypertensive agents, peptides, proteins, particularly cytokines, nucleotides, or a non-toxic salt of said substances.
According to a preferred embodiment of the conjugated polymer according to the present invention, a polymer containing a polyfumarate sequence (A equals CHxe2x95x90CH) may be linked directly or via a polymeric or peptide arm to an active principle by a covalent bond. Examples of active principles include anti-tumour agents such as taxol, cis-platins and doxorubicins.
The invention also relates to a process for the preparation of the block polymers having the general formula (I). This process is characterised in that polyester sequences are polymerised with polyethylene glycol sequences and in that, optionally, polycarbonate sequences are introduced into the polymer
According to a preferred embodiment of the process according to the invention, polyester sequences are prepared by polycondensation of dicarboxylic acid with diols. The introduction of the carbonate sequences may be carried out in the following manner: the terminal hydroxyl groups of a monomer or of an oligomer with a bis-hydroxy end group are converted to an activated derivative by reaction with a compound having the formula:
Xxe2x80x94COxe2x80x94X
where X represents Cl or imidazole.
These activated derivatives react with hydroxyl compounds to obtain carbonate groups.
By using the reagents in a stoichiometric quantity, it is possible to obtain polymers with a high molecular weight. To this end, it is important to have good equivalence between the COX end groups of the activated oligomer and the OH end groups of the diols. In fact, for polycondensation reactions (assuming that the yield of the reaction is 100%), the molecular mass by weight is given by the equation:
Xn=(1+r)/(1xe2x88x92r)
where Xn is the average degree of polymerisation and
r is the ratio of complementary functional groups during the reaction.
The invention also relates to the use of a block polymer having the general formula (I) in pharmaceutical compositions. However, said polymers are not limited to such a use. They may be used in all fields requiring controlled biodegradability, for example, in agriculture.